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1.  EGFR-directed antibodies increase the risk of severe infection in cancer patients 
BMC Medicine  2015;13:37.
Monoclonal antibodies directed to the epidermal growth factor receptor (EGFR) have a role in the management of several solid tumors, alone or in combination with chemotherapy or radiation therapy. Recognized toxicities have included hypersensitivity reactions, rash, hypomagnesemia, and constitutional symptoms, but the possibility that the agents lead to immunosuppression or increase the risk of infection has only recently been recognized. Two latest meta-analyses, including the recently published article by Qi et al., highlight the increased risk of severe infections with EGFR-directed monoclonal antibodies. Further studies are needed to better identify the association between EGFR-directed monoclonal antibody treatment and infection, as well as to elucidate the mechanism of this toxicity and to develop tools to identify patients at increased risk for these complications. In the meantime, awareness of the role of EGFR-directed antibodies in increased infection risk may have implications for dose modification strategies in both clinical trial design and the practice of oncology.
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PMCID: PMC4336483
EGFR; Infection; Monoclonal antibody
2.  Drug therapy for patients with systolic heart failure after the PARADIGM-HF trial: in need of a new paradigm of LCZ696 implementation in clinical practice 
BMC Medicine  2015;13:35.
Heart failure represents a primary cause of morbidity and mortality in older people and despite significant therapeutic advances, it is still characterized by important unmet needs, thus remaining a challenging field of clinical research. The recent PARADIGM-HF trial compared the novel compound LCZ696, a combination of the angiotensin receptor blocker valsartan and the neprilysin inhibitor sacubitril, versus the angiotensin-converting enzyme inhibitor enalapril in 8,442 patients with symptomatic chronic systolic heart failure. LCZ696 led to a 20% reduction in the rate of death or hospitalization for heart failure and a 16% reduction in the rate of all-cause death compared to enalapril at 3.5 years of follow-up. Despite those impressive results, the clinical application of this novel agent that requires the substitution of a cornerstone of current heart failure therapy, the angiotensin-converting enzyme inhibitors, should follow careful steps as imposed by the study design, the recruited population and the outcome in specific patient subgroups. Further insights into the effects of LCZ696 will be provided by the ongoing PARAGON-HF trial in patients with diastolic heart failure.
PMCID: PMC4334585
Heart failure; Therapy; LCZ696; PARADIGM-HF; Angiotensin-converting enzyme inhibitor; Neprilysin; Valsartan; Sacubitril
3.  Developing a guideline to standardize the citation of bioresources in journal articles (CoBRA) 
BMC Medicine  2015;13:33.
Many biomedical publications refer to data obtained from collections of biosamples. Sharing such bioresources (biological samples, data, and databases) is paramount for the present governance of research. Recognition of the effort involved in generating, maintaining, and sharing high quality bioresources is poorly organized, which does not encourage sharing. At publication level, the recognition of such resources is often neglected and/or highly heterogeneous. This is a true handicap for the traceability of bioresource use. The aim of this article is to propose, for the first time, a guideline for reporting bioresource use in research articles, named CoBRA: Citation of BioResources in journal Articles.
As standards for citing bioresources are still lacking, the members of the journal editors subgroup of the Bioresource Research Impact Factor (BRIF) initiative developed a standardized and appropriate citation scheme for such resources by informing stakeholders about the subject and raising awareness among scientists and in science editors’ networks, mapping this topic among other relevant initiatives, promoting actions addressed to stakeholders, launching surveys, and organizing focused workshops.
The European Association of Science Editors has adopted BRIF’s suggestion to incorporate statements on biobanks in the Methods section of their guidelines. The BRIF subgroup agreed upon a proposed citation system: each individual bioresource that is used to perform a study and that is mentioned in the Methods section should be cited as an individual “reference [BIORESOURCE]” according to a delineated format. The EQUATOR (Enhancing the QUAlity and Transparency Of health Research) network mentioned the proposed reporting guideline in their “guidelines under development” section.
Evaluating bioresources’ use and impact requires that publications accurately cite such resources. Adopting the standard citation scheme described here will improve the quality of bioresource reporting and will allow their traceability in scientific publications, thus increasing the recognition of bioresources’ value and relevance to research.
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PMCID: PMC4331335
Biobanks; Bioresource; Bioresource Research Impact Factor; CoBRA; Data sharing; Guideline; Open policies; Repository; Standardized citation; Traceability
4.  The National Institutes of Health and guidance for reporting preclinical research 
BMC Medicine  2015;13:34.
The quality of reporting clinical and preclinical research is not optimal. Reporting guidelines can help make reports of research more complete and transparent, thus increasing their value and making them more useful to all readers. Getting reporting guidelines into practice is complex and expensive, and involves several stakeholders, including prospective authors, peer reviewers, journal editors, guideline developers, and implementation scientists. Working together will help ensure their maximum uptake and penetration. We are all responsible for helping to ensure that all research is reported so completely that it is of value to everybody.
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PMCID: PMC4332445
Implementation; Preclinical research; Quality of reporting; Reporting guidelines
5.  E-cigarettes: methodological and ideological issues and research priorities 
BMC Medicine  2015;13:32.
Cigarette combustion, rather than either tobacco or nicotine, is the cause of a public health disaster. Fortunately, several new technologies that vaporize nicotine or tobacco, and may make cigarettes obsolete, have recently appeared. Research priorities include the effects of vaporizers on smoking cessation and initiation, their safety and toxicity, use by non-smokers, dual use of vaporizers and cigarettes, passive vaping, renormalization of smoking, and the development of messages that effectively communicate the continuum of risk for tobacco and nicotine products. A major difficulty is that we are chasing a moving target. New products constantly appear, and research results are often obsolete by the time they are published. Vaporizers do not need to be safe, only safer than cigarettes. However, harm reduction principles are often misunderstood or rejected. In the context of a fierce ideological debate, and major investments by the tobacco industry, it is crucial that independent researchers provide regulators and the public with evidence-based guidance. The methodological and ideological hurdles on this path are discussed in this commentary.
PMCID: PMC4330977
Tobacco use disorder; Electronic nicotine delivery devices (ENDS); Electronic cigarette; E-cigarette; Nicotine; Smoking; Tobacco
6.  Diagnosis and management of hyponatraemia: AGREEing the guidelines 
BMC Medicine  2015;13:31.
Hyponatraemia is a common electrolyte disorder associated with significant complications and controversies regarding its optimal management. Clinical practice guidelines and consensus statements have attempted to provide clinicians with evidence-based diagnostic and treatment strategies for hyponatraemia. Recently published guidance documents differ in their methods employed to review the quality of available evidence. Nagler et al. used the Appraisal of Guideline for Research and Evaluation (AGREE II) instrument in a systematic review of guidelines and consensus statements for the diagnosis and management of hyponatraemia. Nagler and colleagues highlighted the variability in methodological rigour applied to guideline development and inconsistencies between publications in relation to management of hyponatraemia (including the recommended rate of correction of a low serum sodium concentration). These differences could cause confusion for practising physicians managing patients with hyponatraemia.
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PMCID: PMC4328520
Hyponatraemia; Guidelines; Systematic review
7.  Proxy markers of serum retinol concentration, used alone and in combination, to assess population vitamin A status in Kenyan children: a cross-sectional study 
BMC Medicine  2015;13:30.
Serum retinol concentration determined by high-performance liquid chromatography (HPLC) is recommended by the World Health Organization to assess population vitamin A status. This assay is expensive, technically demanding and rarely available in developing countries. Our objective was a) to assess the diagnostic performance of proxy markers in detecting vitamin A deficiency and b) to derive decision rules based on these markers to estimate vitamin A deficiency prevalence.
A survey was conducted in 15 rural primary schools in Eastern Province, Kenya, with 375 children aged 6 to 12 years (25 randomly selected per school). Serum retinol concentration <0.70 μmol/L by HPLC was used to define vitamin A deficiency. Proxy markers for vitamin A deficiency were serum concentrations of retinol binding protein (RBP), transthyretin, retinol measured by fluorometry and RBP:transthyretin molar ratio.
The prevalence of vitamin A deficiency (HPLC) was 18%. Transthyretin and RBP showed the best diagnostic performance individually, with area-under-the-curve (AUC) values of 0.96 and 0.93. When combined, and with C-reactive protein added, the AUC increased to 0.98. A simple decision rule {(−15.277 × [RBP, μmol/L] - 7.013 × [Transthyretin, μmol/L] + 0.367 × [C-reactive protein, mg/L] + 24.714) > 0.496} yielded prevalence estimates of vitamin A deficiency that is unbiased by diagnostic error.
The combination of transthyretin, RBP and C-reactive protein concentrations could eventually replace retinol concentration by HPLC in resource-poor settings as the preferred method to assess the population burden of vitamin A deficiency.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0256-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4324407
Vitamin A deficiency; Discriminant analysis; ROC curve; Sensitivity and specificity; Predictive value of tests; Retinol; Retinol binding protein; Transthyretin; Inflammation; Diagnosis
8.  Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses 
BMC Medicine  2015;13:28.
The genesis of severe fatigue and disability in people following acute pathogen invasion involves the activation of Toll-like receptors followed by the upregulation of proinflammatory cytokines and the activation of microglia and astrocytes. Many patients suffering from neuroinflammatory and autoimmune diseases, such as multiple sclerosis, Parkinson’s disease and systemic lupus erythematosus, also commonly suffer from severe disabling fatigue. Such patients also present with chronic peripheral immune activation and systemic inflammation in the guise of elevated proinflammtory cytokines, oxidative stress and activated Toll-like receptors. This is also true of many patients presenting with severe, apparently idiopathic, fatigue accompanied by profound levels of physical and cognitive disability often afforded the non-specific diagnosis of chronic fatigue syndrome.
Multiple lines of evidence demonstrate a positive association between the degree of peripheral immune activation, inflammation and oxidative stress, gray matter atrophy, glucose hypometabolism and cerebral hypoperfusion in illness, such as multiple sclerosis, Parkinson’s disease and chronic fatigue syndrome. Most, if not all, of these abnormalities can be explained by a reduction in the numbers and function of astrocytes secondary to peripheral immune activation and inflammation. This is also true of the widespread mitochondrial dysfunction seen in otherwise normal tissue in neuroinflammatory, neurodegenerative and autoimmune diseases and in many patients with disabling, apparently idiopathic, fatigue. Given the strong association between peripheral immune activation and neuroinflammation with the genesis of fatigue the latter group of patients should be examined using FLAIR magnetic resonance imaging (MRI) and tested for the presence of peripheral immune activation.
It is concluded that peripheral inflammation and immune activation, together with the subsequent activation of glial cells and mitochondrial damage, likely account for the severe levels of intractable fatigue and disability seen in many patients with neuroimmune and autoimmune diseases.This would also appear to be the case for many patients afforded a diagnosis of Chronic Fatigue Syndrome.
PMCID: PMC4320458
Immune; Inflammation; Oxidative stress; Toll-like receptor; Fatigue; Mitochondria; Multiple sclerosis; Chronic fatigue syndrome; Parkinson’s disease
9.  Delays in the post-marketing withdrawal of drugs to which deaths have been attributed: a systematic investigation and analysis 
BMC Medicine  2015;13:26.
Post-marketing withdrawal of medicinal products because of deaths can be occasioned by evidence obtained from case reports, observational studies, randomized trials, or systematic reviews. There have been no studies of the pattern of withdrawals of medicinal products to which deaths have been specifically attributed and the evidence that affects such decisions. Our objectives were to identify medicinal products that were withdrawn after marketing in association with deaths, to search for the evidence on which withdrawal decisions were based, and to analyse the delays involved and the worldwide patterns of withdrawal.
We searched the World Health Organization’s Consolidated List of [Medicinal] Products, drug regulatory authorities’ websites, PubMed, Google Scholar, and textbooks on adverse drug reactions. We included medicinal products for which death was specifically mentioned as a reason for withdrawal from the market. Non-human medicines, herbal products, and non-prescription medicines were excluded. One reviewer extracted the data and a second reviewer verified them independently.
We found 95 drugs for which death was documented as a reason for withdrawal between 1950 and 2013. All were withdrawn in at least one country, but at least 16 remained on the market in some countries. Withdrawals were more common in European countries; few were recorded in Africa (5.3%). The more recent the launch date, the sooner deaths were reported. However, in 47% of cases more than 2 years elapsed between the first report of a death and withdrawal of the drug, and the interval between the first report of a death attributed to a medicinal product and eventual withdrawal of the product has not improved over the last 60 years.
These results suggest that some deaths associated with these products could have been avoided. Manufacturers and regulatory authorities should expedite investigations when deaths are reported as suspected adverse drug reactions and consider early suspensions. Increased transparency in the publication of clinical trials data and improved international co-ordination could shorten the delays in withdrawing dangerous medicinal products after reports of deaths and obviate discrepancies in drug withdrawals in different countries.
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Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0262-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4318389  PMID: 25651859
Death; Drug withdrawal; Review; Voluntary recall
10.  Why are there deadly drugs? 
BMC Medicine  2015;13:27.
Some drugs eventually have to be removed from the market because of a negative benefit-to-harm ratio, including an excess of mortality. Drug safety is the result of multiple factors, commencing with how clinical trials are designed, the information generated by and/or hidden through these trials, trial analysis by drug regulatory authorities (DRAs) and the amount of information that DRAs choose to release, the amount of published information regarding drug safety, the effectiveness of postmarket surveillance systems in recognizing and reporting adverse drug reactions, and the structure of DRAs such as the United States Food and Drug Administration and its equivalent in other countries. This commentary will look at each of these issues in order to highlight the problems in the current approach to drug safety and finally indicate how some of these deficiencies should be addressed.
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PMCID: PMC4318445  PMID: 25656293
Adverse drug reactions; Clinical trials; Drug regulatory authority; Drug safety; Pharmaceutical company
11.  Stepping Stones Triple P: the importance of putting the findings into context 
BMC Medicine  2015;13:25.
The Stepping Stones Triple P (SSTP) parenting program is an evidence-based program for parents of children with a disability. A trial of SSTP was recently published in BMC Medicine, which reported results of a randomized controlled trial comparing SSTP to care-as-usual. Although the paper described what should be an important replication trial of SSTP, there are significant shortcomings to the scientific approach of the reporting that need to be addressed. The paper initially cites only a few published SSTP studies and describes evidence for the efficacy of the program as “very scarce”. A meta-analysis of studies evaluating SSTP published prior to submission of this paper was not cited. The results are inconsistent with previous evidence for SSTP, yet the authors provide scant interpretation for this inconsistency. Similarly, the unusually high dropout rate of 49% was not adequately explained. The claims that previous research has only been conducted by the developers, has not included children with intellectual disability, and has not used care-as-usual comparison groups, are inaccurate. This commentary explores these issues further in order to place the findings from the recent trial into context.
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PMCID: PMC4316393  PMID: 25649871
Commentary; Evidence; Stepping Stones Triple P
12.  Global malaria eradication and the importance of Plasmodium falciparum epidemiology in Africa 
BMC Medicine  2015;13:23.
The global agenda for malaria has, once again, embraced the possibility of eradication. As history has shown, there will be no single magic bullet that can be applied to every epidemiological setting. Africa has a diverse malaria ecology, lending itself to some of the highest disease burden areas of the world and a wide range of clinical epidemiological patterns making control with our current tools challenging. This commentary highlights why the epidemiology of Plasmodium falciparum malaria in Africa should not be forgotten when planning an eradication strategy, and why forgetting Africa will, once again, be the single largest threat to any hope for global eradication.
PMCID: PMC4314741  PMID: 25644195
Africa; Eradication; Malaria; Plasmodium falciparum
13.  The impact of maternal smoking during pregnancy on depressive and anxiety behaviors in children: the Norwegian Mother and Child Cohort Study 
BMC Medicine  2015;13:24.
Maternal smoking during pregnancy (MSDP) is associated with multiple adverse childhood outcomes including externalizing behaviors. However, the association between MSDP and internalizing (anxiety and depressive) behaviors in offspring has received less investigation. We aimed to assess the association between MSDP and childhood internalizing (anxiety and depressive) behaviors in a very large, well-characterized cohort study.
We assessed the association between MSDP and internalizing behaviors in offspring utilizing information drawn from 90,040 mother-child pairs enrolled in the Norwegian Mother and Child Cohort Study. Mothers reported smoking information, including status and frequency of smoking, twice during pregnancy. Mothers also reported their child’s internalizing behaviors at 18 months, 36 months, and 5 years. Associations between MSDP and childhood internalizing behaviors, including dose-response and timing of smoking in pregnancy, were assessed at each time point.
MSDP was associated with increased internalizing behaviors when offspring were aged 18 months (B = 0.11, P <0.001) and 36 months (B = 0.06, P <0.01), adjusting for numerous potential confounders. Higher rates of smoking (e.g., >20 cigarettes per day) were associated with higher levels of internalizing behaviors. Maternal smoking during early pregnancy appeared to be the critical period for exposure.
We found evidence supporting a potential role for MSDP in increasing internalizing (anxiety and depressive) behaviors in offspring. We also found evidence supportive of a possible causal relationship, including dose-dependency and support for a predominant role of early pregnancy exposure. Further investigation utilizing genetically informed designs are warranted to assess this association.
PMCID: PMC4314755  PMID: 25644294
Anxiety; Depression; Cigarette smoking; Pregnancy; Obstetrics; Psychiatry
14.  Innocent lives lost and saved: the importance of blood transfusion for children in sub-Saharan Africa 
BMC Medicine  2015;13:22.
Severe anemia in children is a leading indication for blood transfusion worldwide. Severe anemia, defined by the World Health Organization as a hemoglobin level <5 g/dL, is particularly common throughout sub-Saharan Africa. Analysis of data from the Fluid Expansion as Supportive Therapy (FEAST) trial offers new insights into the importance of blood transfusion for children with severe anemia. The principal findings of this analysis include the observations that life-threatening anemia in children is a frequent presenting condition in East Africa; that delays in transfusion therapy are lethal; and that inadequate transfusion is probably more common than currently recognized. The findings of this new study highlight the need for changes in blood inventory management in sub-Saharan hospitals and the need for more research on transfusion therapy for children in peril.
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PMCID: PMC4313467  PMID: 25640864
Transfusion; sub-Saharan Africa; Severe anemia
15.  Anaemia and blood transfusion in African children presenting to hospital with severe febrile illness 
BMC Medicine  2015;13:21.
Severe anaemia in children is a leading cause of hospital admission and a major cause of mortality in sub-Saharan Africa, yet there are limited published data on blood transfusion in this vulnerable group.
We present data from a large controlled trial of fluid resuscitation (Fluid Expansion As Supportive Therapy (FEAST) trial) on the prevalence, clinical features, and transfusion management of anaemia in children presenting to hospitals in three East African countries with serious febrile illness (predominantly malaria and/or sepsis) and impaired peripheral perfusion.
Of 3,170 children in the FEAST trial, 3,082 (97%) had baseline haemoglobin (Hb) measurement, 2,346/3,082 (76%) were anaemic (Hb <10 g/dL), and 33% severely anaemic (Hb <5 g/dL). Prevalence of severe anaemia varied from 12% in Kenya to 41% in eastern Uganda. 1,387/3,082 (45%) children were transfused (81% within 8 hours). Adherence to WHO transfusion guidelines was poor. Among severely anaemic children who were not transfused, 52% (54/103) died within 8 hours, and 90% of these deaths occurred within 2.5 hours of randomisation. By 24 hours, 128/1,002 (13%) severely anaemic children had died, compared to 36/501 (7%) and 71/843 (8%) of those with moderate and mild anaemia, respectively. Among children without severe hypotension who were randomised to receive fluid boluses of 0.9% saline or albumin, mortality was increased (10.6% and 10.5%, respectively) compared to controls (7.2%), regardless of admission Hb level. Repeat transfusion varied from ≤2% in Kenya/Tanzania to 6 to 13% at the four Ugandan centres. Adverse reactions to blood were rare (0.4%).
Severe anaemia complicates one third of childhood admissions with serious febrile illness to hospitals in East Africa, and is associated with increased mortality. A high proportion of deaths occurred within 2.5 hours of admission, emphasizing the need for rapid recognition and prompt blood transfusion. Adherence to current WHO transfusion guidelines was poor. The high rates of re-transfusion suggest that 20 mL/kg whole blood or 10 mL/kg packed cells may undertreat a significant proportion of anaemic children. Future evaluation of the impact of a larger volume of transfused blood and optimum transfusion management of children with Hb of <6 g/dL is warranted.
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Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0246-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4313469  PMID: 25640706
Africa; Anaemia; Blood transfusion; Children; FEAST trial; Malaria; Sepsis
16.  The science of clinical practice: disease diagnosis or patient prognosis? Evidence about “what is likely to happen” should shape clinical practice 
BMC Medicine  2015;13:20.
Diagnosis is the traditional basis for decision-making in clinical practice. Evidence is often lacking about future benefits and harms of these decisions for patients diagnosed with and without disease. We propose that a model of clinical practice focused on patient prognosis and predicting the likelihood of future outcomes may be more useful.
Disease diagnosis can provide crucial information for clinical decisions that influence outcome in serious acute illness. However, the central role of diagnosis in clinical practice is challenged by evidence that it does not always benefit patients and that factors other than disease are important in determining patient outcome. The concept of disease as a dichotomous ‘yes’ or ‘no’ is challenged by the frequent use of diagnostic indicators with continuous distributions, such as blood sugar, which are better understood as contributing information about the probability of a patient’s future outcome. Moreover, many illnesses, such as chronic fatigue, cannot usefully be labelled from a disease-diagnosis perspective. In such cases, a prognostic model provides an alternative framework for clinical practice that extends beyond disease and diagnosis and incorporates a wide range of information to predict future patient outcomes and to guide decisions to improve them. Such information embraces non-disease factors and genetic and other biomarkers which influence outcome.
Patient prognosis can provide the framework for modern clinical practice to integrate information from the expanding biological, social, and clinical database for more effective and efficient care.
PMCID: PMC4311412  PMID: 25637245
Clinical decision-making; Contested diagnoses; Diagnosis; Evidence-based medicine; Information; Outcomes of care; Overdiagnosis; Prognosis; Stratified medicine
17.  Time-to-infection by Plasmodium falciparum is largely determined by random factors 
BMC Medicine  2015;13:19.
The identification of protective immune responses to P. falciparum infection is an important goal for the development of a vaccine for malaria. This requires the identification of susceptible and resistant individuals, so that their immune responses may be studied. Time-to-infection studies are one method for identifying putative susceptible individuals (infected early) versus resistant individuals (infected late). However, the timing of infection is dependent on random factors, such as whether the subject was bitten by an infected mosquito, as well as individual factors, such as their level of immunity. It is important to understand how much of the observed variation in infection is simply due to chance.
We analyse previously published data from a treatment-time-to-infection study of 201 individuals aged 0.5 to 78 years living in Western Kenya. We use a mathematical modelling approach to investigate the role of immunity versus random factors in determining time-to-infection in this cohort. We extend this analysis using a modelling approach to understand what factors might increase or decrease the utility of these studies for identifying susceptible and resistant individuals.
We find that, under most circumstances, the observed distribution of time-to-infection is consistent with this simply being a random process. We find that age, method for detection of infection (PCR versus microscopy), and underlying force of infection are all factors in determining whether time-to-infection is a useful correlate of immunity.
Many epidemiological studies of P. falciparum infection assume that the observed variation in infection outcomes, such as time-to-infection or presence or absence of infection, is determined by host resistance or susceptibility. However, under most circumstances, this distribution appears largely due to the random timing of infection, particularly in children. More direct measurements, such as parasite growth rate, may be more useful than time-to-infection in segregating patients based on their level of immunity.
PMCID: PMC4311447  PMID: 25633459
Blood-stage immunity; Malaria; Mathematical modelling; Plasmodium falciparum; Time-to-infection
18.  In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver 
BMC Medicine  2015;13:18.
Maternal smoking is one of the most important modifiable risk factors for low birthweight, which is strongly associated with increased cardiometabolic disease risk in adulthood. Maternal smoking reduces the levels of the methyl donor vitamin B12 and is associated with altered DNA methylation at birth. Altered DNA methylation may be an important mechanism underlying increased disease susceptibility; however, the extent to which this can be induced in the developing fetus is unknown.
In this retrospective study, we measured concentrations of cobalt, vitamin B12, and mRNA transcripts encoding key enzymes in the 1-carbon cycle in 55 fetal human livers obtained from 11 to 21 weeks of gestation elective terminations and matched for gestation and maternal smoking. DNA methylation was measured at critical regions known to be susceptible to the in utero environment. Homocysteine concentrations were analyzed in plasma from 60 fetuses.
In addition to identifying baseline sex differences, we found that maternal smoking was associated with sex-specific alterations of fetal liver vitamin B12, plasma homocysteine and expression of enzymes in the 1-carbon cycle in fetal liver. In the majority of the measured parameters which showed a sex difference, maternal smoking reduced the magnitude of that difference. Maternal smoking also altered DNA methylation at the imprinted gene IGF2 and the glucocorticoid receptor (GR/NR3C1).
Our unique data strengthen studies linking in utero exposures to altered DNA methylation by showing, for the first time, that such changes are present in fetal life and in a key metabolic target tissue, human fetal liver. Furthermore, these data propose a novel mechanism by which such changes are induced, namely through alterations in methyl donor availability and changes in 1-carbon metabolism.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0251-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4310040  PMID: 25630355
DNA methylation; Liver; Maternal smoking; Vitamin B12
19.  Effects on mortality of a nutritional intervention for malnourished HIV-infected adults referred for antiretroviral therapy: a randomised controlled trial 
BMC Medicine  2015;13:17.
Malnourished HIV-infected African adults are at high risk of early mortality after starting antiretroviral therapy (ART). We hypothesized that short-course, high-dose vitamin and mineral supplementation in lipid nutritional supplements would decrease mortality.
The study was an individually-randomised phase III trial conducted in ART clinics in Mwanza, Tanzania, and Lusaka, Zambia. Participants were 1,815 ART-naïve non-pregnant adults with body mass index (BMI) <18.5 kg/m2 who were referred for ART based on CD4 count <350 cells/μL or WHO stage 3 or 4 disease. The intervention was a lipid-based nutritional supplement either without (LNS) or with additional vitamins and minerals (LNS-VM), beginning prior to ART initiation; supplement amounts were 30 g/day (150 kcal) from recruitment until 2 weeks after starting ART and 250 g/day (1,400 kcal) from weeks 2 to 6 after starting ART. The primary outcome was mortality between recruitment and 12 weeks of ART. Secondary outcomes were serious adverse events (SAEs) and abnormal electrolytes throughout, and BMI and CD4 count at 12 weeks ART.
Follow-up for the primary outcome was 91%. Median adherence was 66%. There were 181 deaths in the LNS group (83.7/100 person-years) and 184 (82.6/100 person-years) in the LNS-VM group (rate ratio (RR), 0.99; 95% CI, 0.80–1.21; P = 0.89). The intervention did not affect SAEs or BMI, but decreased the incidence of low serum phosphate (RR, 0.73; 95% CI, 0.55–0.97; P = 0.03) and increased the incidence of high serum potassium (RR, 1.60; 95% CI, 1.19–2.15; P = 0.002) and phosphate (RR, 1.23; 95% CI, 1.10–1.37; P <0.001). Mean CD4 count at 12 weeks post-ART was 25 cells/μL (95% CI, 4–46) higher in the LNS-VM compared to the LNS arm (P = 0.02).
High-dose vitamin and mineral supplementation in LNS, compared to LNS alone, did not decrease mortality or clinical SAEs in malnourished African adults initiating ART, but improved CD4 count. The higher frequency of elevated serum potassium and phosphate levels suggests high-level electrolyte supplementation for all patients is inadvisable but the addition of micronutrient supplements to ART may provide clinical benefits in these patients.
Trial registration
PACTR201106000300631, registered on 1st June 2011.
PMCID: PMC4308881  PMID: 25630368
Antiretroviral therapy; Body mass index; Electrolytes; HIV; Malnutrition; Micronutrients
20.  Haemoglobin level at birth is associated with short term outcomes and mortality in preterm infants 
BMC Medicine  2015;13:16.
Blood volume and haemoglobin (Hb) levels are increased by delayed umbilical cord clamping, which has been reported to improve clinical outcomes of preterm infants. The objective was to determine whether Hb level at birth was associated with short term outcomes in preterm infants born at ≤32 weeks gestation.
Data were collected retrospectively from electronic records: Standardised Electronic Neonatal Database, Electronic Patient Record, Pathology (WinPath), and Blood Bank Electronic Database. The study was conducted in a tertiary perinatal centre with around 5,500 deliveries and a neonatal unit admission of 750 infants per year. All inborn preterm infants of 23 to 32 weeks gestational age (GA) admitted to the neonatal unit from January 2006 to September 2012 were included.
The primary outcomes were intra-ventricular haemorrhage, necrotising entero-colitis, broncho-pulmonary dysplasia, retinopathy of prematurity, and death before discharge. The secondary outcomes were receiving blood transfusion and length of intensive care and neonatal unit days. The association between Hb level (g/dL) at birth and outcomes was analysed by multiple logistic regression adjusting for GA and birth weight (BWt).
Overall, 920 infants were eligible; 28 were excluded because of missing data and 2 for lethal congenital malformation. The mean (SD) GA was 28.3 (2.7) weeks, BWt was 1,140 (414) g, and Hb level at birth was 15.8 (2.6) g/dL.
Hb level at birth was significantly associated with all primary outcomes studied (P <0.001) in univariate analyses. Once GA and BWt were adjusted for, only death before discharge remained statistically significant; the OR of death for infants with Hb level at birth <12 g/dL compared with those with Hb level at birth of ≥18 g/dL was 4.1 (95% CI, 1.4–11.6). Hb level at birth was also significantly associated with blood transfusion received (P <0.01) but not with duration of intensive care or neonatal unit days.
Low Hb level at birth was significantly associated with mortality and receiving blood transfusion in preterm infants born at ≤32 weeks gestation. Further studies are needed to determine the association between Hb level at birth and long-term neurodevelopmental outcomes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0247-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4307132  PMID: 25622597
Haemoglobin; Mortality; Outcome; Preterm
21.  Validating estimates of prevalence of non-communicable diseases based on household surveys: the symptomatic diagnosis study 
BMC Medicine  2015;13:15.
Easy-to-collect epidemiological information is critical for the more accurate estimation of the prevalence and burden of different non-communicable diseases around the world. Current measurement is restricted by limitations in existing measurement systems in the developing world and the lack of biometry tests for non-communicable diseases. Diagnosis based on self-reported signs and symptoms (“Symptomatic Diagnosis,” or SD) analyzed with computer-based algorithms may be a promising method for collecting timely and reliable information on non-communicable disease prevalence. The objective of this study was to develop and assess the performance of a symptom-based questionnaire to estimate prevalence of non-communicable diseases in low-resource areas.
As part of the Population Health Metrics Research Consortium study, we collected 1,379 questionnaires in Mexico from individuals who suffered from a non-communicable disease that had been diagnosed with gold standard diagnostic criteria or individuals who did not suffer from any of the 10 target conditions. To make the diagnosis of non-communicable diseases, we selected the Tariff method, a technique developed for verbal autopsy cause of death calculation. We assessed the performance of this instrument and analytical techniques at the individual and population levels.
The questionnaire revealed that the information on health care experience retrieved achieved 66.1% (95% uncertainty interval [UI], 65.6–66.5%) chance corrected concordance with true diagnosis of non-communicable diseases using health care experience and 0.826 (95% UI, 0.818–0.834) accuracy in its ability to calculate fractions of different causes. SD is also capable of outperforming the current estimation techniques for conditions estimated by questionnaire-based methods.
SD is a viable method for producing estimates of the prevalence of non-communicable diseases in areas with low health information infrastructure. This technology can provide higher-resolution prevalence data, more flexible data collection, and potentially individual diagnoses for certain conditions.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0245-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4306245  PMID: 25620318
Automated methods; Mexico; Non-communicable diseases; Non-communicable diseases prevalence; Questionnaire
22.  Quality of oral anticoagulation with phenprocoumon in regular medical care and its potential for improvement in a telemedicine-based coagulation service – results from the prospective, multi-center, observational cohort study thrombEVAL 
BMC Medicine  2015;13:14.
The majority of studies on quality of oral anticoagulation (OAC) therapy with vitamin K-antagonists are performed with short-acting warfarin. Data on long-acting phenprocoumon, which is frequently used in Europe for OAC therapy and is considered to enable more stable therapy adjustment, are scarce. In this study, we aimed to assess quality of OAC therapy with phenprocoumon in regular medical care and to evaluate its potential for optimization in a telemedicine-based coagulation service.
In the prospective observational cohort study program thrombEVAL we investigated 2,011 patients from regular medical care in a multi-center cohort study and 760 patients from a telemedicine-based coagulation service in a single-center cohort study. Data were obtained from self-reported data, computer-assisted personal interviews, and laboratory measurements according to standard operating procedures with detailed quality control. Time in therapeutic range (TTR) was calculated by linear interpolation method to assess quality of OAC therapy. Study monitoring was carried out by an independent institution.
Overall, 15,377 treatment years and 48,955 international normalized ratio (INR) measurements were analyzed. Quality of anticoagulation, as measured by median TTR, was 66.3% (inte rquartile range (IQR) 47.8/81.9) in regular medical care and 75.5% (IQR 64.2/84.4) in the coagulation service (P <0.001). Stable anticoagulation control within therapeutic range was achieved in 63.8% of patients in regular medical care with TTR at 72.1% (IQR 58.3/84.7) as compared to 96.4% of patients in the coagulation service with TTR at 76.2% [(IQR 65.6/84.7); P = 0.001)]. Prospective follow-up of coagulation service patients with pretreatment in regular medical care showed an improvement of the TTR from 66.2% (IQR 49.0/83.6) to 74.5% (IQR 62.9/84.2; P <0.0001) in the coagulation service. Treatment in the coagulation service contributed to an optimization of the profile of time outside therapeutic range, a 2.2-fold increase of stabile INR adjustment and a significant decrease in TTR variability by 36% (P <0.001).
Quality of anticoagulation with phenprocoumon was comparably high in this real-world sample of regular medical care. Treatment in a telemedicine-based coagulation service substantially improved quality of OAC therapy with regard to TTR level, frequency of stable anticoagulation control, and TTR variability.
Trial registration, unique identifier NCT01809015, March 8, 2013.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0268-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4333875  PMID: 25616558
Coagulation service; Epidemiology; Health care research; Oral anticoagulation; Quality of therapy; Telemedicine
23.  Could low grade bacterial infection contribute to low back pain? A systematic review 
BMC Medicine  2015;13:13.
Recently, there has been both immense interest and controversy regarding a randomised, controlled trial which showed antibiotics to be effective in the treatment of chronic low back pain (disc herniation with Modic Type 1 change). While this research has the potential to result in a paradigm shift in the treatment of low back pain, several questions remain unanswered. This systematic review aims to address these questions by examining the role of bacteria in low back pain and the relationship between bacteria and Modic change.
We conducted electronic searches of MEDLINE and EMBASE and included studies that examined the relationship between bacteria and back pain or Modic change. Studies were rated based on their methodological quality, a best-evidence synthesis was used to summarise the results, and Bradford Hill’s criteria were used to assess the evidence for causation.
Eleven studies were identified. The median (range) age and percentage of female participants was 44.7 (41–46.4) years and 41.5% (27–59%), respectively, and in 7 of the 11 studies participants were diagnosed with disc herniation. Nine studies examined the presence of bacteria in spinal disc material and all identified bacteria, with the pooled estimate of the proportion with positive samples being 34%. Propionibacterium acnes was the most prevalent bacteria, being present in 7 of the 9 studies, with median (minimum, maximum) 45.0% (0–86.0) of samples positive. The best evidence synthesis found moderate evidence for a relationship between the presence of bacteria and both low back pain with disc herniation and Modic Type 1 change with disc herniation. There was modest evidence for a cause-effect relationship.
We found that bacteria were common in the spinal disc material of people undergoing spinal surgery. There was moderate evidence for a relationship between the presence of bacteria and both low back pain with disc herniation and Modic Type 1 change associated with disc herniation and modest evidence for causation. However, further work is needed to determine whether these organisms are a result of contamination or represent low grade infection of the spine which contributes to chronic low back pain.
PMCID: PMC4320560  PMID: 25609421
Bacteria; Disc; Infection; Low back pain; Modic change; Systematic review
24.  Renal function during long-term lithium treatment: a cross-sectional and longitudinal study 
BMC Medicine  2015;13:12.
The effects of lithium treatment on renal function have been previously shown, albeit with discrepancies regarding their relevance. In this study, we examined glomerular filtration rate in patients treated with lithium for up to 33 years.
All lithium patients registered from 1980 to 2012 at a Lithium Clinic were screened. Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine concentration using the Modification of Diet in Renal Disease Study Group equation. A cross-sectional evaluation of the last available eGFR of 953 patients was carried out using multivariate regression analysis for gender, current age, and duration of lithium treatment. Survival analysis was subsequently applied to calculate the time on lithium needed to enter the eGFR ranges 45 to 59 mL/min/1.73 m2 (G3a) or 30 to 44 mL/min/1.73 m2 (G3b). Finally, 4-year follow-up of eGFR was examined in subgroups of patients who, after reduction to an eGFR lower than 45 mL/min/1.73 m2 either i) continued lithium at the same therapeutic range or ii) discontinued lithium or continued at concentrations below the therapeutic range (0.5 mmol/L).
In the cross-sectional evaluation, eGFR was found to be lower in women (by 3.47 mL/min/1.73 m2), in older patients (0.73 mL/min/1.73 m2 per year of age), and in patients with longer lithium treatment (0.73 mL/min/1.73 m2 per year). Half of the patients treated for longer than 20 years had an eGFR lower than 60 mL/min/1.73 m2. The median time on lithium taken to enter G3a or G3b was 25 years (95% CI, 23.2–26.9) and 31 years (95% CI, 26.6–35.4), respectively. Progression of renal failure throughout the 4-year follow-up after a reduction to an eGFR lower than 45 mL/min/1.73 m2 did not differ between the subgroup who continued lithium as before and the subgroup who either discontinued lithium or continued at concentrations below the therapeutic range.
Duration of lithium treatment is to be added to advancing age as a risk factor for reduced glomerular filtration rate. However, renal dysfunction tends to appear after decades of treatment and to progress slowly and irrespective of lithium continuation.
PMCID: PMC4300557  PMID: 25604586
Chronic kidney disease; Glomerular filtration; Lithium treatment
25.  Major dietary patterns and risk of frailty in older adults: a prospective cohort study 
BMC Medicine  2015;13:11.
There is emerging evidence of the role of certain nutrients as risk factors for frailty. However, people eat food, rather than nutrients, and no previous study has examined the association between dietary patterns empirically derived from food consumption and the risk of frailty in older adults.
This is a prospective cohort study of 1,872 non-institutionalized individuals aged ≥60 years recruited between 2008 and 2010. At baseline, food consumption was obtained with a validated diet history and, by using factor analysis, two dietary patterns were identified: a ‘prudent’ pattern, characterized by high intake of olive oil and vegetables, and a ‘Westernized’ pattern, with a high intake of refined bread, whole dairy products, and red and processed meat, as well as low consumption of fruit and vegetables. Participants were followed-up until 2012 to assess incident frailty, defined as at least three of the five Fried criteria (exhaustion, weakness, low physical activity, slow walking speed, and unintentional weight loss).
Over a 3.5-year follow-up, 96 cases of incident frailty were ascertained. The multivariate odds ratios (95% confidence interval) of frailty among those in the first (lowest), second, and third tertile of adherence to the prudent dietary pattern were 1, 0.64 (0.37–1.12), and 0.40 (0.2–0.81), respectively; P-trend = 0.009. The corresponding values for the Westernized pattern were 1, 1.53 (0.85–2.75), and 1.61 (0.85–3.03); P-trend = 0.14. Moreover, a greater adherence to the Westernized pattern was associated with an increasing risk of slow walking speed and weight loss.
In older adults, a prudent dietary pattern showed an inverse dose-response relationship with the risk of frailty while a Westernized pattern had a direct relationship with some of their components. Clinical trials should test whether a prudent pattern is effective in preventing or delaying frailty.
PMCID: PMC4298966  PMID: 25601152
Cohort study; Diet; Frailty; Older adults; Spain

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